JP2016106146A - Continuous administration of l-dopa, dopa decarboxylase inhibitors, catechol-o-methyl transferase inhibitors and compositions for the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutically acceptable composition for use in treating a neurological or movement disorder.SOLUTION: A pharmaceutically acceptable composition comprises 2.5 to 7% by weight levodopa, 0 to 2% by weight carbidopa, 5 to 18% by weight arginine, and 0.25 to 3% by weight ascorbic acid or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

Detailed Description of the Invention

〔Technical field〕
The present invention relates to pharmaceutical compositions useful for the treatment of neurological or movement disorders such as Parkinson's disease, and methods for treating such disorders by substantially continuous subcutaneous administration of said compositions. provide.

[Background Technology]
Parkinson's disease is a degenerative condition characterized by a decrease in the concentration of the neurotransmitter dopamine in the brain. Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine), unlike dopamine, is a direct metabolic precursor of dopamine that can cross the blood brain barrier, most commonly dopamine in the brain. Used to repair concentration. For the past 40 years, levodopa has been the most effective therapeutic agent for treating Parkinson's disease.

  However, levodopa has a short half-life in plasma and provides pulsatile dopaminergic stimulation, even under the best general current standard treatment. Long-term treatment is thus complicated by movement fluctuations and dyskinesias that can be a significant source of disability for some patients. A therapeutic strategy that can ultimately deliver levodopa / dopamine to the brain more continuously and physiologically provides the advantages of standard levodopa with reduced motor complications, and Parkinson's disease and other neurological or There is a greater need from patients suffering from movement disorders (Olanow CW; Mov. Dis. 2008, 23 (Suppl. 3): S613-S622). Sustained release oral levodopa formulations have been developed, but such preparations have been found to be at most as effective as standard tablets. Continuous administration of levodopa by intraduodenal administration or infusion has also been attempted using portable pumps or patches. Such treatments, especially intraduodenal administration, are extremely invasive and inconvenient.

  The metabolic conversion of levodopa to dopamine is catalyzed by the aromatic L-amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain and brain capillaries. Due to the possibility of levodopa's extracerebral metabolism, it is necessary to administer large doses of levodopa, which results in high extracerebral concentrations of dopamine that cause nausea in some patients. Thus, levodopa usually reduces the levodopa dose required for clinical response by 60-80% and thus prevents its side effects to some extent by inhibiting the conversion of levodopa to extra-brain dopamine, such as carbidopa or benserazide It is administered at the same time as the oral administration of the dopa decarboxylase inhibitor. Various oral formulations combined with inhibitors of enzymes related to metabolic degradation of levodopa, such as decarboxylase inhibitors such as carbidopa and benserazide, catechol-O-methyltransferase (COMT) inhibitors such as entacapone and tolcapone, and moclobemide Monoamine oxidase (MAO) -A or MAO-B inhibitors such as rasagiline or selegiline or safinamide are well known. Currently available oral drugs include SINEMET® and SINEMET® CR sustained release tablets containing carbidopa or levodopa, STALEVO® tablets containing carbidopa, entacapone and levodopa, and levodopa and benserazide. Contains MADOPAR® tablets containing. There remains an urgent need for methods and compositions that can provide continuous stimulation of L-dopa to more effectively treat movement disorders such as Parkinson's disease. Nevertheless, stable liquid formulations having an effective concentration in a volume suitable for use, for example, for subcutaneous or transdermal delivery have not been realized so far.

[Summary of the Invention]
The present disclosure relates generally to a pharmaceutically acceptable composition comprising, in part, 1) an active ingredient comprising carbidopa and at least about 4% by weight levodopa, arginine and optional meglumine. Such a composition may have a pH of about 9.1 to about 9.8 at 25 ° C.

  In some embodiments, disclosed compositions having arginine have a molar ratio of active ingredient to arginine of about 1: 1.8 to about 1: 3.5, or about 1: 2.3. Also good. In exemplary embodiments, the disclosed compositions may comprise from about 4% to about 12% or more levodopa and / or 1% to about 6% by weight carbidopa, such as about 1 % To about 2% by weight of carbidopa.

  When meglumine is present in the disclosed composition, the molar ratio of active ingredient to arginine can be, for example, from about 1: 1.1 to about 1: 1.9, and the molar ratio of active ingredient to meglumine. May be from about 1: 0.3 to about 1: 1.5, for example, the molar ratio of active ingredient to meglumine is about 1: 0.3 to about 1: 1.2, or, for example, It may be about 1: 0.4 or about 1: 1.1. Such contemplated compositions may comprise from about 2.0% to about 11% by weight meglumine. A contemplated composition as described above may comprise, for example, 10% to about 35% by weight arginine.

The disclosed compositions may further comprise an agent that inhibits the formation of oxidation products, for example, such agents include ascorbic acid, Na ascorbate, L-cysteine, N-acetylcysteine (NAC), glutathione _(GSH), Na ₂ -EDTA, may be selected Na 2 -EDTA-Ca, and combinations thereof. For example, the pharmaceutically acceptable compositions disclosed herein may further comprise ascorbic acid or a pharmaceutically acceptable salt thereof in an exemplary embodiment. In another or further embodiment, the disclosed composition may comprise sodium bisulfite.

  As used herein, a pharmaceutically acceptable composition comprising levodopa, arginine and optional meglumine and ascorbic acid or a pharmaceutically acceptable salt thereof is contemplated, eg, the composition comprises about 4% by weight % To about 12% by weight of levodopa. The salt of ascorbic acid can be selected, for example, from the group consisting of ascorbate, sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate. For example, the disclosed pharmaceutically acceptable compositions include ascorbic acid or a pharmaceutically acceptable salt thereof, such as sodium ascorbate, eg, about 0.25% by weight or more of ascorbic acid or a pharmaceutically acceptable salt thereof. About 0.2 wt.% To about 3 wt.% Ascorbic acid or a pharmaceutically acceptable salt thereof, or about 0.5 wt.% To about 1 wt.% Ascorbic acid or a pharmaceutically acceptable salt thereof. Salt may be included. In some embodiments, contemplated pharmaceutically acceptable compositions have a molar ratio of levodopa to arginine of about 1: 1.8 to about 1: 3.5, such as 1: 2.3. May be.

  Such contemplated compositions may in some embodiments further comprise carbidopa, for example 1% to about 2% carbidopa. In such embodiments, the combined molar ratio of levodopa and carbidopa to arginine may be from about 1: 1.8 to about 1: 3.5, such as about 1: 2.3. Such pharmaceutically acceptable compositions may have a pH of from about 9.1 to about 9.8 at 25 ° C.

  The contemplated compositions and formulations disclosed herein may be liquid at room temperature, for example. In some embodiments, the disclosed pharmaceutically acceptable compositions may further comprise entacapone or tolcapone.

  The disclosed pharmaceutically acceptable formulations may be stable at 25 ° C. ± 5 ° C. for at least 2 weeks and / or may be stable at −20 ° C. ± 5 ° C. for at least 2 months, for example. Good.

  Herein, in one embodiment, a transdermal patch suitable for administration of the disclosed pharmaceutically acceptable compositions is contemplated.

  Also provided herein is a method of treating a neurological or movement disorder, such as Parkinson's disease, in a patient in need of treatment comprising a composition disclosed herein, eg, levodopa and / or carbidopa. A method is provided comprising administering a liquid composition to the patient. Also, herein, in one embodiment, a neurological disorder, or a disorder characterized by a decrease in the level of dopamine in the patient's brain, and / or a disease or disorder such as, for example, a disorder such as Parkinson's disease A method is provided for treatment of a method comprising the administration (eg, substantially continuous administration) of a disclosed composition. In one embodiment, continuous administration may include transdermal, intradermal, subcutaneous, intravenous, subarachnoid, epidural, intracranial, or intraduodenal administration, for example, use of an infusion pump. . Such methods may further comprise orally administering levodopa and / or carbidopa, and optionally entacapone or tolcapone.

  The disclosed compositions may be administered subcutaneously and / or, for example, substantially continuously. Such subcutaneous administration may involve the use of one or more infusion pumps and / or transdermal and / or dermal patches. For example, the disclosed methods can be at least about 0.01 ml / hour to about 0.2 ml / hour, or at least about 0.07 ml / hour, or, for example, about 0.15 ml / hour during the day or during a patient's activity. Time and the rate at which the disclosed composition is administered from about 0 ml / hour to about 0.075 0.25 ml / hour at rest or sleep may be included. Alternatively, the disclosed compositions may be administered intraduodenum or intravenously.

  In some embodiments, the method comprising administering subcutaneously includes, for example, from about 0.20 ml / hour to about 2.0 ml / hour, such as about 1.0 ± 0. Of one or more infusion pumps at a rate to administer the composition of 5 ml / hour, or about 1.25 ± 0.5 ml / hour, and about 0 ml / hour to about 0.5 ml / hour at night or at rest Including use.

  Also provided herein is (i) carbidopa, at least 4 wt% levodopa, arginine and optional meglumine, or (ii) levodopa, arginine, optional meglumine, and ascorbic acid or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable compositions for use in the treatment of neurological or movement disorders are provided. In one embodiment, the neurological or movement disorder is Parkinson's disease.

  As used herein, in one embodiment, from about 2.5 wt% to about 7 wt% levodopa, from about 0 wt% to about 2 wt% carbidopa, from about 5 wt% to about 18 wt% arginine, and about Disclosed is a pharmaceutically acceptable formulation comprising 0.25 wt% to about 3 wt% ascorbic acid or a pharmaceutically acceptable salt thereof.

  In one embodiment, a pharmaceutically acceptable formulation comprising about 8% to about 12% levodopa, about 1% to about 3% carbidopa, about 15% to about 35% arginine Is contemplated. In another embodiment, from about 8 wt% to about 12 wt% levodopa, from about 1 wt% to about 3 wt% carbidopa, and from about 12 wt% to about 15 wt% arginine, and from about 3 wt% to about A pharmaceutically acceptable formulation comprising 10% by weight meglumine is provided. Such compositions may further comprise about 0.25 to 3% by weight ascorbic acid.

  Also included herein are arginine and at least about 7% by weight entacapone or tolcapone, such as at least about 8% by weight, or at least about 10% by weight, or from about 7% to about 12% by weight entacapone or tolcapone. A pharmaceutically acceptable liquid composition is provided. For example, the disclosed compositions may have entacapone or tolcapone and arginine in a molar ratio of about 1: 0.5 to about 1: 2.5, such as about 1: 1 to about 1: 1.5. . Such a liquid composition may have a pH of from about 6 to about 9 at 25 ° C. and / or may be substantially stable for at least 48 hours at 25 ° C.

As used herein, in one embodiment, a process for preparing a stable solution comprising levodopa and / or carbidopa and arginine, comprising:
Providing levodopa and / or carbidopa and arginine to form a powder mixture;
Adding water to the powder mixture to form a suspension;
Heating the suspension at a temperature of about 40 ° C. to about 90 ° C. to form a solution;
Cooling the solution to provide a stable liquid composition;
A process is provided. In some embodiments, heating the suspension further comprises stirring the suspension.

  The present disclosure may be used, at least in part, to form a stable liquid formulation in which arginine is suitable, for example, for continuous subcutaneous, transdermal, intradermal, intravenous and / or intraduodenal administration. Related to the discovery that carbidopa and / or levodopa and / or salt of entacapone or tolucapone can be formed. Such disclosed compositions can administer carbidopa, entacapone, tolcapone and / or levodopa substantially continuously to patients in need thereof. For example, herein, substantially continuous administration of levodopa and optional entacapone or tolcapone and substantially continuous administration of a dopa decarboxylase inhibitor such as carbidopa is substantially continuous. Stimulating L-dopa and thus, for example, extending the effectiveness of a levodopa oral dosage regimen and / or reducing the daily dose of levodopa or eliminating the need for oral levodopa, while Or disclosed is a composition related to the disclosed discovery that it can effectively treat a neurological disorder.

[Brief description of the drawings]
FIG. 1 shows the effect of carbidopa on levodopa stability in vitro and ex vivo. A. 6 wt% levodopa and arginine solutions with or without carbidopa at various concentrations (2%, 1.5%, 1%, 0.5%) were tested for physical stability in vitro did. The results show that carbidopa prevents dark yellow formation in the presence of air (right small vial), depending on dose, 0.5% in the absence of air (N _{2 in} headspace). % Carbidopa was sufficient to inhibit this color formation (large vial on the left side of the figure). B. A 7 wt% levodopa and arginine solution with or without 2 wt% carbidopa was administered into the subcutaneous tissue of 5x5 cm fresh pig full thickness skin. The right side shows inhibition of oxidation by use of a levodopa formulation containing carbidopa.

  FIG. 2 shows that the presence of 1% carbidopa in levodopa solution reduces the severity and extent of local levodopa-dependent subcutaneous toxicity in pigs.

  FIG. 3 is a graph showing the effect of carbidopa on the pharmacokinetics of levodopa in pigs. A: Graph showing the plasma concentration of levodopa after continuous subcutaneous administration of 6% levodopa with various amounts of carbidopa. B: is a graph showing the correlation between the plasma steady state concentration of levodopa and the combined concentration of carbidopa obtained after continuous subcutaneous administration of the levodopa / carbidopa formulation. C: is a graph showing the correlation between carbidopa plasma steady state concentration and carbidopa formulation concentration after continuous subcutaneous administration of levodopa / carbidopa formulation.

  FIG. 4 shows the effect of various agents on ex vivo levodopa oxidation in the subcutaneous tissue of porcine skin samples after subcutaneous administration of a levodopa / carbidopa formulation.

  FIG. 5A shows continuous subcutaneous (SC) entacapone (200 mg / 24 hours) and / or carbidopa (CD) versus plasma concentration of levodopa (ng / ml) after oral administration of Sinemet (100/25 levodopa / carbidopa) in pigs. ) (40 mg / 24 hours).

  FIG. 5B shows the effect of continuous SC CD (40 mg / 24 hours) and / or levodopa (LD) (140 mg / 24 hours) administration on plasma concentrations of levodopa after oral administration of Sinemet (100/25) in pigs. It is a graph to show.

  FIG. 6 shows the effect of carbidopa on local subcutaneous toxicity of levodopa after 24 hours of continuous subcutaneous administration at 0.16 ml / hour in pigs.

[Mode for Carrying Out the Invention]
Disclosed herein, in one embodiment, is a room temperature stable liquid composition comprising arginine salts of levodopa (eg, arginine and levodopa) and optionally carbidopa. Such disclosed compositions can facilitate invasive delivery of effective amounts of levodopa, carbidopa, and / or other active agents, such as entacapone or tolcapone, to a patient in a minimally invasive manner. Further, the disclosed formulations have a pH suitable for, for example, transdermal, subcutaneous, intravenous, subarachnoid, epidural, intracranial, or intraduodenal administration.

  For example, herein, a substantially constant inhibition of COMT activity can be obtained after administration, thereby increasing the half-life of administered levodopa and substantially increasing the pulsatility of levodopa plasma levels. Formulations and methods are provided that can reduce and avoid low trough levels of plasma levodopa.

  Further, the present specification unexpectedly provides stable dissolution of higher concentrations (eg, greater than 2% by weight) of levodopa, eg, at an acceptable pH, for example for substantially continuous subcutaneous or transdermal administration. A formulation of levodopa and optional carbidopa is also provided that also enables. Such formulations can also be suitable for intravenous, intradermal, oral or intraduodenal administration. For example, the present specification provides formulations and methods that can obtain a substantially constant plasma levodopa concentration, substantially reduce the pulsatility of levodopa plasma levels, and avoid low trough levels of plasma levodopa Is done.

  The treatment strategy of continuous levodopa and carbidopa (and / or entacapone or tolcapone) administration according to the present invention can simulate L-dopa substantially continuously. For example, the treatments and / or methods of the present invention extend the levodopa oral dosage regimen from about 2 times / day to about 3 times / day and / or reduce the daily dose of levodopa and / or levodopa and carbidopa. Oral administration can be reduced or even eliminated.

(Composition)
Herein, in one embodiment, a liquid formulation comprising arginine salt of levodopa or a liquid formulation comprising arginine and levodopa is provided. As used herein, in one embodiment, a liquid comprising levodopa and arginine in a molar ratio of levodopa: arginine of about 1: 1.5 to about 1: 2.5, or about 1: 2 to about 1: 2.3. The formulation or, for example, if such a liquid composition further comprises carbidopa, about 1: 2 to about 1.3.5, or about 1: 1.8 to about 1: 3.5 carbidopa: arginine. A liquid formulation comprising is provided.

  Such levodopa and arginine formulations or solutions have a pharmaceutically acceptable pH for subcutaneous administration, for example from about 8 to about 10, such as from about 9.1 to about 9.8, such as 9.2 to 9. It may have a pH of 6. The disclosed formulations having levodopa and arginine may comprise at least about 7%, 8%, 9% or more levodopa, such as about 10%, 20% or more levodopa. May be included. In some embodiments, the disclosed formulations are about 2.5 weight percent to about 10 weight percent levodopa, 4 weight percent to about 7 weight percent levodopa, or about 7.5 weight percent to about 12 weight percent. Of levodopa, or about 5% to about 30% or about 10% to about 20% by weight of levodopa, and further about 9% to about 20% arginine, or about 9% Percent to about 30 weight percent arginine, such as about 10 weight percent to about 18 weight percent arginine, about 10 weight percent to about 20 weight percent or about 15 weight percent to about 30 weight percent or more arginine, or about 12 weight percent , 13, 14, or 15 weight parse It may include the adoption of arginine. For example, arginine is present in a contemplated formulation as a ratio of arginine: total active ingredients (which may include, for example, levodopa, carbidopa, etc.) from about 1.5: 1 to about 3: 1, for example 1.8: 1. To about 3.5: 1 molar ratio.

  For example, herein, a pharmaceutical having a pH of about 9.1 to about 9.8 at 25 ° C. comprising the active ingredients levodopa and carbidopa (eg, about 4 wt% or more levodopa), and arginine and / or meglumine. An acceptable composition is disclosed. For example, contemplated compositions having levodopa and arginine may further comprise carbidopa, for example, at least about 1%, at least about 2%, at least about 4%, such as from about 2% to about 4%. Weight percent carbidopa may also be included. For example, as used herein, arginine and from about 2% to about 12% or more levodopa (eg, from about 4% to about 10%, from about 4% to about 7%, about 5% % To about 10% by weight, or from about 6% to about 11% by weight levodopa, or from about 5% to about 20% by weight levodopa), and from about 1% to about 6% by weight, from about 1% by weight Compositions comprising about 2% by weight (eg, about 1.25% or about 1.5%), or about 2% to about 5% or about 2% to about 4% carbidopa are provided. The When administered subcutaneously and / or dermally, such compositions with levodopa and carbidopa are minimal compared to, for example, subcutaneous or dermal administration of a composition comprising only levodopa (eg, levodopa / arginine composition). Can cause limited local tissue damage. In addition, such levodopa and arginine compositions can have higher stability when further containing carbidopa (eg, unwanted oxidation production over time compared to compositions having only levodopa and arginine). Cannot form things).

  In another embodiment, the disclosed formulations may include an amino sugar such as meglumine, which can, for example, replace some or all of the arginine present in the formulation. For example, disclosed herein is a formulation comprising levodopa and / or carbidopa and meglumine. Also contemplated herein are levodopa meglumine salt and carbidopa meglumine salt. In one embodiment, the composition comprises arginine and has active agents such as levodopa and carbidopa, wherein the molar ratio of active agent to arginine is less than about 1: 2, and the stability of such compositions In order to improve the exemplary composition, the exemplary composition may further comprise meglumine, for example in a ratio of active agent to meglumine of about 1: 0.3 to about 1.1.5. For example, provided herein is a composition having levodopa or carbidopa (or combinations thereof), arginine, and meglumine as active ingredients, wherein the molar ratio of active ingredient to arginine is from about 1: 1.1 to about 1 The molar ratio of active ingredient to meglumine is about 1: 0.3 to about 1: 1.2 (eg, about 1: 0.4, 1: 0.5, 1: 0.8, 1: 1.1). Contemplated compositions include levodopa (eg, about 4% to about 10% or more), carbidopa (eg, about 0.5% to about 3%, eg, about 1% or 2% by weight) About 9 wt.% To about 16 wt.% Arginine, and about 2 wt.% To about 10 wt.% Meglumine.

  Also provided herein is a formulation comprising, in one embodiment, levodopa, arginine, and / or carbidopa, and optionally, an agent that inhibits, for example, the formation of oxidation products. Such a formulation may be a liquid having a pH of about 9.1 to 9.8 at room temperature. For example, provided herein are compositions comprising ascorbic acid or a salt thereof.

In one embodiment, the disclosed compositions may further comprise one or more agents that inhibit the formation of oxidation products. Such agents may be, for example, tyrosinase inhibitors and / or o-quinone scavengers and / or Cu ⁺⁺ chelators and / or antioxidants. In some embodiments, carbidopa may function as an agent that inhibits the formation of oxidation products. For example, contemplated formulations may include o-quinone scavengers such as, but not limited to, N-acetyl cysteine, glutathione, ascorbic acid, Na ascorbate, and / or L-cysteine. In one embodiment, the formulation comprises captopril, methimazole, quercetin, arbutin, aloesin, N-acetylglucosamine, retinoic acid, α-tocopheryl ferrate, MAP (ascorbyl phosphate phosphate), substrate analogs (eg, benzoic acid). sodium, L- phenylalanine), ^{Cu ++} chelating agent, for example, _{Na 2 -EDTA, Na 2 -EDTA-} Ca, DMSA ( succimer), DPA (D-penicillamine), trientine-HCl, dimercaprol, clioquinol, thiosulfate An agent selected from one or more of tyrosinase inhibitors such as sodium, TETA, TEPA, curcumin, neocuproin, tannin, and / or cuprizone may be included. Other contemplated antioxidants that can form part of the disclosed formulations are sulfites (eg, sodium bisulfite or sodium metabisulfite), di-tert-butylmethylphenol, tert-butyl-methoxyphenol. , Ubiquinone including, but not limited to, polyphenols, tocophenols, and / or caffeic acid.

  Provided herein, in a specific embodiment, is a composition comprising levodopa, carbidopa, arginine, optional meglumine, and ascorbic acid or a pharmaceutically acceptable salt thereof. For example, contemplated compositions may further comprise ascorbate, sodium ascorbate, potassium ascorbate, calcium ascorbate, ascorbyl stearate, and / or ascorbyl palmitate. For example, the composition can be about 0.5 weight percent or more (eg, about 0.5 weight percent to about 3 weight percent, or about 0.2 weight percent to about 2 weight percent, or about 0.5 weight percent to about It may contain 1 weight percent, for example about 0.75 weight percent ascorbic acid or a salt thereof.

  Provided herein, in one embodiment, is a pharmaceutically acceptable formulation comprising entacapone (or tolcapone) and arginine that allows for substantially continuous administration of entacapone or tolcapone. For example, provided herein is a stable liquid formulation that includes, for example, entacapone or tolcapone and may be suitable for substantially continuous administration to a patient. Further, such formulations may have a physiologically acceptable pH, such as a pH of about 6 to about 9.5, or about 6.5 to about 8.5, or about 7 to about 8. .

  For example, entacapone (or tolcapone) and arginine are dissolved in an aqueous solution (eg, having a pH of about 6 to 9, eg, about 6.5 to about 8.5, eg, about 7 to 8 at 25 ° C. or 30 ° C.). May be. Alternatively, entacapone (free base) (or tolcapone (free base)) and a basic amino acid salt (eg, arginine and / or lysine) are dissolved together in a liquid (eg, an aqueous liquid) and the disclosed liquid formulation Form. The disclosed liquid formulation may comprise about 2% by weight entacapone or tolcapone, about 4% by weight entacapone or tolcapone, or about 2% to about 12% by weight entacapone or tolcapone, for example about 7% by weight More than about 8% by weight or more than about 10% by weight of entacapone or tolcapone and may contain from about 3% to about 20% or more of entacapone or tolcapone, eg from about 5% to about 8% by weight About 8% to about 12% by weight of entacapone or tolcapone. For example, the liquid formulation contains entacapone and a basic amino acid (eg, arginine) from about 1: 0.5 to about 1: 2.5, or from about 1: 1 to about 1: 2, such as about 1: 1 or 1: It may be included at a molar ratio of 1.5. Such liquid formulations may further comprise carbidopa, such as at least about 2% or at least about 4% carbidopa, such as from about 2% to about 6% or more carbidopa. In another embodiment, such a liquid formulation further comprises levodopa, such as at least about 2%, 3%, 4%, 5%, 6%, or 7% levodopa, such as about 2. 5% to about 12% by weight of levodopa may be included. In an exemplary embodiment, a composition comprising tolcapone or entacapone may further comprise excipients such as alpha, beta or gamma cyclodextrins or derivatives.

  Disclosed liquid formulations (eg, levodopa, carbidopa, entacapone, tolcapone, or a combination of two or more and a liquid composition comprising arginine (and / or meglumine), eg, a disclosed formulation comprising levodopa and arginine) May be stable at 25 ° C. for 24 hours, 48 hours, 7 days, or longer. For example, exemplary liquid formulations have an about 1: 1 molar ratio of entacapone: arginine (or tolcapone: arginine) from about 5% to about 15%, or from about 6% to about 12%, or 6%. % To about 10% by weight of entacapone. Such entacapone, arginine liquid formulations can be more stable, and in some embodiments can be stable for 7 days compared to a liquid composition comprising a lysine or histidine salt of entacapone. In one embodiment, a disclosed formulation comprising levodopa and arginine can be stable at room temperature, such as at 20 ° C. to 30 ° C., such as at 25 ° C. for at least 1 week, or at least 2 weeks or more. In one embodiment, the disclosed formulation comprising levodopa and arginine is at or below freezing point, for example at -10 ° C and / or -20 ° C, at -18 ° C, or at -20 ° C to -80 ° C for at least 1 month. Or can be stable for at least 2 months. In this context, the term “stable” means that the formulation does not significantly precipitate from solution and / or that the active agent does not significantly degrade for a considerable period of time.

  In some embodiments, the disclosed liquid formulation or composition is a solution, ie, a substantially homogeneous liquid mixture. Such a liquid mixture may contain water and / or other pharmaceutically acceptable excipients. In another embodiment, the disclosed liquid composition may be substantially non-aqueous.

  In some embodiments, the disclosed liquid formulations are stable for 1 day, 2 days, 3 days, 1 week or 1 month or more at room temperature. In one embodiment of the present invention, the disclosed liquid formulation further comprises, for example, N-methylpyrrolidone (NMP) or polyvinylpyrrolidone (PVP), EDTA (or a salt thereof), cysteine, N-acetylcysteine, and / or sulfite. Contains pharmaceutically acceptable excipients such as sodium hydrogen.

  For example, herein, in one embodiment, from about 4% to about 12% by weight of levodopa, and / or carbidopa (eg, from about 1% to about 6%, or from about 2% to about 6% by weight). And / or Entacapone or Tolcapone (eg, from about 7% to about 12% by weight), and from about 1% to about 40% by weight arginine, from about 0% to about 10% NMP, about 0% A stable liquid formulation is provided comprising from 1% to about 5% by weight PVP and / or from about 0% to about 3.5% by weight of one or more water-soluble antioxidants.

  The invention further provides a stable lyophilized powder comprising arginine salt of levodopa, carbidopa or entacapone, or a combination of two or more of levodopa, carbidopa or entacapone. In one embodiment, such stable lyophilized powder comprises about 20-99% levodopa or entacapone salt, about 0-60% NMP, about 0-15% PVP, and about 0-10% 1 One or more water-soluble antioxidants may be included. The lyophilized powder can be returned to a liquid formulation with water alone or with the addition of water and NMP and may or may not contain an antioxidant.

As used herein, in some embodiments, for example, from about 4 wt% to about 7 wt% levodopa, from about 1 wt% to about 2 wt% carbidopa, and from about 10 wt% to about 18 wt% arginine. Formulations suitable for continuous subcutaneous administration are provided. Such formulations may further in some embodiments, from about 1 wt% of ascorbic acid (or a pharmaceutically acceptable salt thereof), and / or optionally from about 0.2 wt% of Na ₂ EDTA- Ca may be included.

In another embodiment, at least about 8 wt% levodopa (eg, 8% to about 12%), at least about 1.5 wt% carbidopa (eg, about 1.5% to about 3%), and at least about 15 wt% A formulation suitable for intraduodenal or intravenous administration is provided, which comprises 1% arginine (eg, about 15% to about 30%, or about 15% to about 20% by weight). Such formulations may comprise from about 1 wt% of ascorbic acid, and about 0.2 wt% of _Na 2 EDTA-Ca. Also, as used herein, for continuous intraduodenal or intravenous administration, at least about 8% by weight of levodopa (eg, 8% to about 12%), at least about 1.5% by weight of carbidopa (eg, about 1. 5% to about 3%), at least about 10% by weight arginine or about 12% by weight arginine (eg, about 10% to about 15% by weight, or about 12% to about 15% by weight), at least about 3% by weight % Meglumine (eg about 3% to about 8%, or about 3% to about 5%), and optionally about 1% by weight ascorbic acid (or salt thereof), and / or optionally about 0.2% containing Na ₂ EDTA-Ca, formulations suitable for intraduodenal or intravenous administration is provided. Such formulations may contain water.

  The liquid formulations of the present invention may be designed for continuous administration of entacapone, tolcapone, carbidopa and / or levodopa to patients in need thereof. For example, a patient may be continuously administered (eg, subcutaneous, transdermal, intraduodenal, intradermal, or intravenous) a formulation comprising the disclosed entacapone composition, including arginine and entacapone, while A composition comprising carbidopa, carbidopa salt, or carbidopa of a separate composition or of the same composition, eg, in different devices or in separate compartments within the same device, is also substantially continuous. And / or optionally levodopa and / or carbidopa is administered at individual intervals, for example, twice, three times, four times, or five times a day.

  As used herein, “a composition comprising levodopa” or “levodopa composition” optionally refers to a decarboxylase inhibitor, a catechol-O-methyltransferase (COMT) inhibitor, and / or MAO-A or A formulation comprising levodopa with a MAO-B inhibitor is contemplated. For example, a composition comprising levodopa includes a dosage formulation comprising levodopa (or a salt thereof) and optionally other drugs, the dosage formulation being suitable for oral administration, immediate release, controlled release, two-stage release or multi-stage It may be a release formulation.

  The term “decarboxylase inhibitor” refers to an agent that inhibits peripheral metabolism of levodopa to dopamine by dopa decarboxylase inhibitors, eg, aromatic L-amino acid decarboxylase such as carbidopa and benserazide.

  Movement disorder refers to a condition of the nervous system that causes abnormal voluntary or involuntary movement, or slow, reduced movement.

  A neurological disorder is a disorder of the body's nervous system.

  “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, preservatives, antioxidants, which are compatible with pharmaceutical administration. Refers to coatings, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide supplemental, additional or improved therapeutic functions.

  “Pharmaceutically or pharmacologically acceptable” includes molecular entities and compositions that do not produce side effects, allergies, or other deleterious reactions when administered as appropriate to animals or humans. For human administration, the preparations are S. Sterility, pyrogenicity, general safety and purity standards as defined by FDA Office of Biology standards should be met.

  The term “pharmaceutical composition” as used herein includes at least one active agent disclosed herein formulated with one or more pharmaceutically acceptable carriers. Refers to the composition.

  The term “physiologically acceptable pH” refers to the pH of a composition that facilitates administration of the composition to a patient, for example, without significant adverse effects, eg, about 4 to about 9.8 (eg, about 4 ± It is understood to mean a pH of 0.3 to about 9.5 ± 0.3).

  A COMT inhibitor refers to an inhibitor that inhibits the degradation of levodopa to 3-methyldopa by catechol-O-methyltransferase and prolongs the action of levodopa, eg, entacapone or tolcapone. For example, a composition comprising levodopa as contemplated herein may also comprise a decarboxylase inhibitor (carbidopa or benserazide) and an entacapone, such as a “three-step therapeutic agent”.

  MAO-A or MAO-B inhibitors prevent the destruction of dopamine by monoamine oxidases such as moclobemide, rasagiline, selegiline or safinamide, eg rasagiline.

(Kits and devices)
As used herein, one includes a composition as disclosed herein, for example, as disclosed herein, a composition comprising levodopa and carbidopa, and arginine, and optionally A transdermal patch suitable for transdermal or subcutaneous administration of an active agent, which may comprise a composition comprising carbidopa and / or levodopa, is contemplated. Such patches may have one or more compartments that may have the same or different compositions, for example, one compartment may have the disclosed formulation and another compartment may have You may have different disclosed formulations or different active formulations. A transdermal patch refers to any device capable of delivering one or more of the active agents forming the disclosed composition through the skin or mucosa into the patient's bloodstream.

  Also, as used herein, a) a first formulation comprising a disclosed composition comprising carbidopa and arginine, wherein the first formulation is suitable for continuous (eg, dermal or subcutaneous) administration; ) A second formulation comprising levodopa or an arginine salt of levodopa, suitable for continuous administration; optionally c) a third formulation comprising entacapone and arginine, for continuous administration A suitable third formulation and / or optionally d) a fourth formulation comprising tolcapone and arginine, preferably a fourth formulation suitable for continuous administration, optionally e) levodopa and optionally carbidopa A fifth composition suitable for subcutaneous administration; and / or optionally f) a sixth composition comprising levodopa and / or optionally carbidopa, Suitable sixth formulation given; and, g) the formulation a) ~f) kit comprising instructions for at least one dose of is contemplated. Formulations a) -e) may be suitable for continuous administration by any suitable route, such as transdermal, intravenous, subcutaneous, intradermal, intramuscular, or intraduodenum.

  In one embodiment, the first formulation comprises the disclosed carbidopa salt and is suitable for subcutaneous administration. The sixth formulation of the contemplated kit may comprise a composition comprising levodopa, levodopa salt, or levodopa, including, but not limited to, any suitable pill, tablet, dispersible tablet, capsule, liquid, etc. It may be present as an oral dosage form. In one embodiment, the fourth formulation may be in the form of an immediate release, controlled release, or two-stage release oral formulation comprising both levodopa and benserazide, or both levodopa and carbidopa. Such oral formulations in the form of pills, tablets, etc. may comprise a ratio of carbidopa or benserazide to levodopa of about 1:10 to 1: 4, preferably about 1: 4 to 1: 1. Other contemplated second formulations include formulations such as tablets containing, for example, levodopa, carbidopa, and entacapone (or tolcapone), or tablets containing, for example, levodopa arginine salt and / or carbidopa arginine.

  A contemplated kit may include a levodopa arginine salt (and / or carbidopa arginine salt) or a liquid composition having levodopa, carbidopa, and / or entacapone (or a combination), and arginine. Such compositions may be lyophilized powders that can be reconstituted into liquids or liquid formulations, or may form part of a transdermal patch, for example, transdermal, intravenous, subcutaneous, skin It may be designed for continuous administration by any suitable route, including but not limited to, intramuscular, intraduodenal, and the like.

  In another embodiment, the kit includes, but is not limited to, carbidopa and arginine (and optionally levodopa and / or, suitable for continuous administration transdermally, intravenously, subcutaneously, intradermally, intramuscularly, intraduodenum. A first liquid formulation comprising entacapone or tolcapone) and a second formulation in the form of an immediate release, controlled release or two-stage release oral formulation, including, but not limited to, levodopa and carbidopa A second liquid formulation comprising entacapone and arginine (or tolcapone and arginine) suitable for continuous administration intravenously, subcutaneously, intradermally, intramuscularly, intraduodenum.

  In some embodiments, the disclosed liquid composition (eg, including levodopa, arginine and optional carbidopa) may be provided as a pre-filled cartridge suitable for use by, for example, a patient or physician. . For example, herein, the disclosed liquid formulation is a pre-filled cartridge having a cartridge (eg, a single dose or a dose of levodopa and arginine solution (and optional carbidopa) suitable for single administration to a patient) ), A pre-filled cartridge, and a kit with optional instructions are provided.

(Preparation of composition)
A disclosed formulation or composition comprises mixing arginine and / or meglumine with levodopa and / or carbidopa and optionally an antioxidant (including multiple species) in the amounts disclosed above, eg, a powder mixture. It can be prepared by forming. Water may be added to the mixture to form a suspension. The suspension can be prepared, for example, by adding preheated water and / or optionally with stirring in a hot water bath (eg 72 ± 5 ° C.) (eg about 3 minutes, about 5 minutes, Installed for about 10 minutes or more (eg up to about 10 minutes), for example, heated at about 40 ° C. to about 100 ° C., or about 60 ° C. to 90 ° C., eg 72 ± 5 ° C. to form a solution; The solution may be cooled to form a composition. N ₂ may be provided in the container headspace. Then, for example, the mixture may be removed from the hot water bath and cooled to room temperature, for example immediately after that an optional antioxidant (including multiple species) may be added under N ₂ atmosphere followed by stirring. For example, levodopa, carbidopa, and arginine are first mixed together as a powder, a suspension is formed with water, and then heated, such as the preparation described above, stepwise preparation of individual aqueous suspensions of ingredients and subsequent Compared to preparations involving combinations, a more stable solution can be provided.

  The disclosed formulations can be sterilized using, for example, a 0.2 μm filter such as a filter using nylon or PVDF membrane. In some embodiments, the preparation of the disclosed formulations may include certain antioxidants (e.g., when carbidopa and levodopa are present simultaneously and / or other antioxidants (e.g., sodium bisulfite). When prepared using ascorbic acid or a salt thereof, there are fewer undesirable by-products (eg, toxic by-products) or contaminants (eg, hydrazine). In another embodiment, preparation of the disclosed formulation is undesirable when preheated water is added as disclosed above compared to a formulation prepared without the addition of preheated water Less by-products. In another embodiment, levodopa and / or carbidopa cannot be dissolved unless the disclosed preparation procedure is used. Such a disclosed preparation as described above can provide a more stable formulation as compared to a formulation prepared without the addition of hot water or heating.

(Treatment method)
In a further aspect, the present invention is a method for the treatment of a disease or disorder, such as a neurological or movement disorder, comprising substantially continuously administering the disclosed composition and / or levodopa. (Eg, orally administering a levodopa composition, or subcutaneously administering a disclosed levodopa composition, etc.), and, optionally, a therapeutically effective amount of a COMT inhibitor Optionally with a substantially continuous administration of a composition as disclosed herein (e.g., an entacapone composition comprising entacapone and arginine or a tolcapone composition comprising tolcapone and arginine), comprising: A composition comprising a therapeutically effective amount of a decarboxylase inhibitor or salt thereof (eg, including carbidopa and arginine) And which comprises a substantially continuous co-administering to a patient in need thereof. In some embodiments, provided methods may include substantially continuously administering a composition comprising, for example, both carbidopa and entacapone or tolcapone, or two separate compositions (e.g., One with entacapone or tolcapone and one with carbidopa and / or levodopa), for example, may comprise substantially continuous administration of the compositions disclosed herein. As shown in the Examples, patients who received levodopa with continued administration of carbidopa and entacapone have higher plasma levels of levodopa compared to the plasma levels that one skilled in the art would expect from continued administration of carbidopa or entacapone alone. Levels can also be presented.

  For example, the present specification includes oral administration of a composition comprising levodopa and / or carbidopa (and optionally oral administration of a composition comprising a COMT inhibitor) and also as disclosed herein. Or subcutaneous administration of a composition comprising both levodopa and / or carbidopa as disclosed herein (and subcutaneous administration of levodopa and carbidopa involves separate compositions or both levodopa and carbidopa. A method comprising treating a neurological or movement disorder. Such methods can also include subcutaneous administration of levodopa and / or a COMT inhibitor, which can be different formulations or a single formulation.

  Also herein, a composition (eg, a liquid composition) comprising levodopa and optionally carbidopa without the separate (eg, oral) administration of levodopa, which may be sufficient to maintain therapeutic plasma levels of levodopa. A method of treating a neurological or movement disorder comprising substantially continuous subcutaneous or cutaneous administration of (and optionally optionally substantially administering a composition comprising carbidopa) is provided. In one embodiment, the contemplated method is substantially continuous with levodopa and carbidopa (as the same composition or as separate compositions), eg, at a levodopa: carbidopa weight ratio of about 10: 1 to about 1: 1. Administration may also be included. In one embodiment, contemplated methods may include substantially continuously administering levodopa with or without carbidopa and / or oral COMT inhibitor.

  In some embodiments, a composition comprising levodopa (eg, a disclosed liquid composition) is administered at a rate of about 0.07 ml / hour, or such as from about 0.01 ml / hour to about 0.2 ml / hour. May be. Such speed may be constant throughout the day or night, or may vary according to the patient's needs, e.g. reflecting the patient's rest or sleep schedule and wakefulness or higher activity level schedule. May be. For example, a liquid composition as disclosed herein (eg, including levodopa) can be about 0.15 ml / hour in the morning (eg, about 2-3 hours before waking), during the day or during activity (eg, From about 10 hours to about 12 hours) and / or at rest or at night may be administered at a rate of about 0.035 ml / hour. In another embodiment, a liquid composition such as those disclosed herein (eg, a disclosed composition comprising levodopa) is administered during the day or during activity (eg, about 2-3 hours before waking and about (10 hours to about 12 hours) may be administered at a rate of about 1.0 ml / hour, and at rest or at night, for example intraduodenum at a rate of 0 ml / hour to about 0.5 ml / hour. In another embodiment, a liquid composition as disclosed herein (eg, comprising levodopa and arginine) is administered during the day or during an activity period (eg, about 2-3 hours before or after waking and about 10 thereafter. From about 14 hours) to about 1.25 ml / hour (eg about 1.25 ± 0.5 ml / hour) and at rest or at night from about 0 ml / hour to about 0.5 ml / hour (eg about 0.5 ± 0.25 ml / hour).

  Contemplated administration of, for example, carbidopa, entacapone, tolcapone, and / or levodopa, typically according to the disclosed methods, is typically performed for a defined period of time (usually weeks, months, depending on the combination selected). Or for several years). Contemplated treatments include, in part, a dopa decarboxylase inhibitor and optionally a COMT inhibitor (eg, entacapone or tolcapone) administered substantially continuously while levodopa is administered at discrete intervals. Administration of multiple therapeutic agents in a manner, as well as contemplated therapeutic agents, which may be administered at substantially the same composition, or for example, at the same time but as different compositions, or It is intended to encompass administration of at least two therapeutic agents (eg, levodopa and carbidopa, and optionally entacapone or tolcapone, or levodopa and entacapone or tolcapone). Administration can be achieved by any suitable route including, but not limited to, oral, intravenous, intramuscular, intradermal, subcutaneous, transdermal, and direct absorption through mucosal tissue. it can.

  In some embodiments, levodopa can be administered by the same route or by different routes, eg, as compared to administration of a contemplated carbidopa formulation. For example, carbidopa may be administered subcutaneously, for example, substantially continuously, while levodopa may be administered orally, for example, at discrete intervals. In one embodiment, the disclosed liquid carbidopa composition (eg, having carbidopa and arginine) and liquid entacapone composition (eg, having entacapone and arginine) are administered substantially continuously, while comprising levodopa ( As well as one or more other active agents such as dopa decarboxylase inhibitors and / or COMT inhibitors). Oral compositions are administered at separate intervals. Alternatively, for example, both levodopa and carbidopa may be administered subcutaneously or transdermally. The disclosed compositions may be administered substantially continuously over a 12 hour, 1 day, 1 week, or longer period.

  Diseases or disorders characterized by reduced levels of dopamine in the brain as contemplated herein include restless leg syndrome, Parkinson's disease, secondary Parkinson's syndrome, Huntington's disease, Shy Dräger syndrome and carbon monoxide or It is a neurological or movement disorder, including a condition resulting from brain injury, including manganese poisoning. Methods for treating such disorders in patients in need of treatment are provided, for example, by administering (eg, subcutaneously) the disclosed compositions. In one embodiment, the disease to be treated is Parkinson's disease.

  In one embodiment, substantially continuous administration, for example using a liquid formulation, lasted 24 hours at about 10-250 μl / hour, or about 160 ± 40 μl / hour; at about 200 ± 50 μl / hour By a subcutaneous infusion pump (insulin pump) at an average rate of about 0 μl / hour to 80 μl / hour, continued for 16 hours (during wake-up time) and at night (eg 8 hours), or by a transdermal patch Also good. In one embodiment, substantially continuous intravenous or intraperitoneal administration, eg, using a liquid formulation, continues for about 0.2-2 ml / hour, or about 1 ± 0.5 ml / hour for 24 hours; Pump or transdermal patch at an average rate of about 1.0 ± 0.5 ml / hour, continuous for 16 hours (during wake-up time) and at night (eg 8 hours) about 0 ml / hour to 0.5 ml / hour Or, for example, by a combination of delivery devices suitable for subcutaneous, intravenous, subarachnoid or transduodenal.

  The present invention will now be described generally, but is included for the purpose of illustration of certain specific aspects and embodiments of the invention only and is not intended to limit the invention in any manner. Thus, the present invention is more easily understood.

〔Example〕
(Example 1: Preparation of solution / formulation for subcutaneous administration)
A. A preheated 0.1% sodium bisulfite solution was added to carbidopa [ASSIA Ltd. To prepare a 2% carbidopa solution / formulation. Arginine [MERCK] was added to obtain a final molar ratio of CD (carbidopa): arg (arginine) of 1: 1.2. The mixture was stirred at 60 ° C. until complete dissolution was obtained. Heating was stopped and the preparation was cooled to a room temperature pH of 8.5. The solution was filtered using a sterile 0.22 μΜ PVDF membrane.

B. A 10% tolcapone solution / formulation was prepared as follows: each amount of H ₂ O was added to tolcapone [Synfine Research] and arginine was added slowly during stirring to a final molar ratio of 1: 1. To prepare a solution containing 10% tolcapone. The mixture is stirred until complete dissolution is obtained. After cooling, the pH of the solution was 7.8.

C. Each amount of H ₂ O is added to Entacapone [Suven Life Sciences], stirred at 30-35 ° C., and arginine is added slowly to obtain a final molar ratio of 1: 1 to 10% Entacapone. A solution containing was prepared. The mixture is stirred until complete dissolution is obtained. After cooling, the pH of the solution was 6.9. The pH of the lower concentration solution (6%) was 7.8. After preparation, such an entacapone solution can be diluted to a 2%, 3% or 4% by weight formulation.

  Entacapone did not dissolve with other amino acids such as histidine and glutamic acid or in various pH buffers (at concentrations above 1%).

  D. A 7% levodopa / 2% carbidopa solution was prepared by adding a preheated 0.1% sodium bisulfite solution to arginine. Levodopa was added to obtain a final molar ratio of 1: 2 LD: arg. The mixture was stirred at 75-80 ° C. until complete dissolution was obtained. After cooling to 60 ° C., carbidopa and arginine were added to give a final molar ratio of CD (carbidopa): arg (arginine) of 1: 1.2. The mixture was stirred at 60 ° C. until complete dissolution was obtained. After cooling, about 12.5% additional arginine was added to the solution. The pH of the solution was about 9.2.

  E. A 7 wt% levodopa solution was prepared by adding a preheated 0.1% sodium bisulfite solution to arginine. Levodopa was added to obtain a final molar ratio of 1: 2 LD: arg. The mixture was stirred at 75-80 ° C. until complete dissolution was obtained. After cooling, the pH of the solution was about 9.4.

(Example 2: Preparation procedure)
Levodopa (LD) and carbidopa (CD) formulations can be prepared as follows. However, as shown in Table A, the method of preparation greatly affects the physical and chemical stability of the resulting composition.

  Method # 1 (L-Arg solution): L-Arg and Na-Bis (Na sulfite) were dissolved in water. The solution was added to the LD and CD powder. The mixture was heated with stirring at 75 ° C. for 13 minutes until completely dissolved. The LD / CD solution was held at room temperature (RT) for 10 minutes and cooled.

  Method # 2 (all powders together): All powders (LD, CD and L-Arg) were weighed and water containing Na-Bis was added. The suspension was heated with stirring at 75 ° C. for 13 minutes until completely dissolved. The LD / CD solution was held at RT for 10 minutes and cooled.

  Method # 3 (same as # 2, but without Na-Bis preheating): All powders (LD, CD and L-Arg) were weighed together and water was added. The suspension was heated with stirring at 75 ° C. for 13 minutes until completely dissolved. The LD / CD solution was held at RT for 10 minutes and cooled.

  Method # 4 (stepwise preparation): LD and the respective amount of L-Arg were weighed and water and Na-Bis solution were added. The suspension was heated at 75 ° C. for 7 minutes until completely dissolved, followed by standing at RT for 7 minutes. CD and each amount of L-Arg were weighed and LD-arg solution was added at 60 ° C. until completely dissolved. Finally, additional L-Arg was added.

  Method # 5 (same as # 4 but without Na-Bis preheating): LD and the respective amount of L-Arg were weighed and water was added. The suspension was heated at 75 ° C. for 7 minutes until completely dissolved, followed by standing at RT for 7 minutes. CD and each amount of L-Arg were weighed and LD-arg solution was added at 60 ° C. until completely dissolved. Finally, additional L-Arg was added.

  After cooling, all formulations by all methods were divided into 3 vials and water, Na-Bis solution or Na-Bis-Arg solution was added to each vial. Physical and chemical stability was evaluated and is shown in Tables A1 and A2.

  At the end of the preparation and after 5 days of stability at RT, the formulations were sampled for HPLC analysis. Recovery after 5 days at RT was calculated relative to T = 0.

  The results in Tables A1 and A2 clearly show that the method of formulation preparation has a great impact on its physical and chemical stability. The formulation of Method # 3 shows significantly greater stability.

Example 3: Effect of arginine on long-term stability of levodopa and levodopa / carbidopa compositions
The procedure outlined in Example 2 and different concentrations of arginine and / or amino sugar (eg meglumine) and / or sugar (eg dextrose) and / or base (NaOH) or another basic amino acid (eg lysine, histidine) A liquid formulation containing levodopa, carbidopa and arginine was prepared using a comparative study on formulations containing The results are shown in Table B.

  Table B shows that arginine forms stable solutions with high concentrations of levodopa and carbidopa (> 2.5%) at molar ratios lower than 1: 2.5, while these with other basic amino acids LD. It does not even dissolve under conditions. At a 1: 2 molar ratio of LD / CD to arginine, the solution does not have long-term stability unless meglumine or another counterion is used, and meglumine reduces the molar ratio of arginine to LD / CD. Can be used for.

  A liquid formulation was prepared by weighing all powders (LD, CD and L-Arg) and adding water preheated to 73 ± 3 ° C. The suspension was placed in a 73 ± 3 ° C. water bath and stirred for 10 minutes until completely dissolved. The LD / CD solution was held at RT for 10 minutes and cooled. Ascorbic acid was then added. The solution was divided into glass vials and held at + 25 ° C. and −20 ° C. for the specified period. Prior to analysis, frozen vials were allowed to stand at RT until completely thawed. The formulation was then mixed and subjected to stability analysis.

  Table C shows the effect of 1-arginine on long-term physical and chemical stability at + 25 ° C and -20 ° C.

  A liquid formulation was prepared by weighing all powders (LD, CD and L-Arg) and adding water preheated to 73 ± 3 ° C. The suspension was placed in a 73 ± 3 ° C. water bath and stirred for 10 minutes until completely dissolved. The LD / CD solution was held at RT for 10 minutes and cooled. Ascorbic acid was then added. The solution was divided into glass vials and held at + 25 ° C. and −20 ° C. for the specified period. Prior to analysis, frozen vials were allowed to stand at RT until completely thawed. The formulation was then mixed and subjected to stability analysis.

  Tables C1-C6 show that there is a correlation between the molar ratio of arginine to LD / CD and stability, and in general, compositions with more arginine have longer stability. The LD / CD: arginine solution (1:> 9.1 molar ratio) is stable for at least 1 month at RT and −20 ± 5 ° C. The solution is stable even at very high solids concentrations (over 45% in total).

  Formulations containing 6 / 1.5% and 5.4 / 1.5% LD / CD and various L-Arg concentrations to investigate the effect of pH and L-arginine concentration on the physical stability of the solution Were titrated with acetic acid (100%) or lactic acid (85%). Table D shows the results.

  Table E shows the physical and chemical stability of the 6 / 1.5 / 14.8% LD / CD / Arg formulation used in the stability test shown in Table D after 3 weeks of preparation.

  Table D shows that ascorbic acid can reduce the pH by 0.1 to 0.15 units compared to Na ascorbate and that other organic acids can further reduce the pH of the formulation. . However, physical stability test results indicate that the formulation is not significantly stable at pH <9.15 ± 0.5. A formulation containing Na ascorbate appears to be more stable than a formulation containing ascorbic acid at a given L-arginine concentration. Thus, it is suggested that excess acid can result in a precipitate in the absence of the appropriate amount of L-Arg.

Example 4: Stability of a levodopa formulation containing carbidopa in vitro and ex vivo
The effect of carbidopa on levodopa formulation was investigated. Levodopa (LD) formulations were prepared using 0 wt%, 0.5 wt%, 1 wt%, 1.5 wt% and 2 wt% carbidopa (CD) and a constant concentration of arginine. Physical and chemical stability was evaluated as shown in Table F.

The experimental results shown in FIG. 1A (see figure) show that carbidopa prevented the formation of a deep yellow in the presence of air, depending on the dose. In the absence of air (N ₂ present in the headspace), 0.5% CD was sufficient to inhibit this color formation. It is suggested that CD inhibits LD oxidation in vitro. The experimental results shown in Table F indicate that carbidopa has no significant effect on the chemical stability of levodopa. Also, to prevent precipitation, the ratio between arginine and all active ingredients is important, indicating that the physical stability of the formulation is dependent on the relative concentration of arginine.

  In additional experiments, LD formulations were prepared using 0%, 0.5%, 1% and 2% CD and their respective concentrations of arginine. Physical and chemical stability was evaluated and the results are shown in Table G.

  In the presence of the appropriate concentration of L-arginine, as shown in Table G, all ex vivo formulations were stable for at least 1 month at RT after thawing.

  The effect of carbidopa on the stability of the levodopa formulation is shown in FIG. A 7% LD-arginine solution with or without 2% CD was continuously administered at 5 ° C. to 5 × 5 cm fresh pig full thickness skin at 0.08 ml / h × 18 h at 37 ° C. The right side of FIG. 1 shows the lack of black by-product formation, suggesting that CD can inhibit LD oxidation ex vivo, as well as o-quinone and melanin formation. .

(Example 5: Stability of carbidopa formulation containing levodopa)
The effect of levodopa on carbidopa stability was investigated. Table H shows the results.

  Table H shows that CD was less sensitive to oxidation and degradation and was more stable in the presence of LD. R. T.A. The impurity areas at 4.82, 5.65, 12.7, 13.53 and 14.55 increase significantly under aerobic conditions in the absence of LD, T.A. The area of impurities at 4.82 and 13.53 increased even in the absence of oxygen. LD appears to be able to prevent CD degradation.

Example 6 Toxicity and Pharmacokinetics of Levodopa Formulation Containing Carbidopa
The effect of carbidopa on the local toxicity of levodopa was investigated in pigs. A solution containing 6% LD and 0%, 0.5% or 1% CD and the respective amount of arginine (13.5%, 14.2% or 14.8%, respectively) was added at 0.16 ml / h. The pigs were continuously administered SC at 24 h. Each formulation was administered to 2 pigs. A skin sample was then taken 8 ± 1 days later. FIG. 2 shows that the presence of 1% carbidopa reduces the severity and extent of levodopa-dependent toxicity in vivo.

  The effect of carbidopa on the pharmacokinetics of levodopa and carbidopa was investigated. Contains 6% LD and 0%, 0.5%, 1% or 2% CD, and respective amounts of arginine (13.5%, 14.2%, 14.8% or 16.5%, respectively) The solution was SC administered continuously to pigs at 0.16 ml / h × 24 h. FIG. 3 shows that CD has a great effect on the pharmacokinetics of LD. This effect was dose dependent, as in Example 6, and was linear between ± 0.3% CD and ± 1.2% CD.

(Example 7: Effect of tyrosinase inhibitor)
Effects of tyrosinase inhibitors, substrate analogs, Cu ⁺⁺ chelators, and O-quinone scavengers on oxidation to levodopa (LD) following continuous subcutaneous administration of levodopa / carbidopa formulation to the subcutaneous tissue of pig skin at 37 ° C Were tested ex vivo.

  Porcine full thickness skin samples (including subcutaneous tissue) were placed in a 100 ml glass bottle filled to the top with warm PBS in an incubator set at 37 ° C. The skin was in direct contact with PBS and then the skin and bottle were covered with parafilm to protect the inside of the skin from air as much as possible. The formulation was administered subcutaneously using a 22G winged needle and an infusion pump set at 0.08 ml / h.

  A list of various potential levodopa stabilizers and oxidation / degradation / metabolism inhibitors is listed in Table I. The effects of representatives from each group and their combinations were tested ex vivo and are shown in FIG.

  The number of each skin sample corresponds to the numbered formulation administered according to Table J below.

  FIG. 4 shows that ascorbate concentrations above 0.5% were sufficient to inhibit color changes of levodopa and carbidopa in porcine skin samples. Other compounds tested were less effective.

Example 8 Effect of Tyrosinase Inhibitor on In Vivo Subcutaneous Toxicity
The effect of tyrosinase inhibitors on subcutaneous toxicity after 24 hours of subcutaneous administration of LD / CD in pigs was tested 6-11 days after administration. The results are shown in Table K.

Under the experimental conditions used, captopril and / or Ca-Na ₂ EDTA, compared with only 1% ascorbate, it did not have an auxiliary effect in protection against local toxicity.

(Example 9: Plasma level of levodopa after subcutaneous administration)
In this experiment, the objective was to determine plasma levels of LD (levodopa) in pigs following continuous subcutaneous administration of carbidopa, levodopa or entacapone and combinations thereof with oral LD / CD.

  Starting from 15:00 on the first day, Landrace x Large Yorkshire female pig weighing approximately 22 kg, carbidopa combined with oral LD / CD100 / 25 and arginine as described above , Levodopa or entacapone and combinations thereof were treated with the respective test formulations and continuously administered subcutaneously via a skin patch (Omnipod®) at a rate of 0.08 ml / h.

  Table L shows the treatment protocol for each group. Formulations were prepared as in Examples 1 and 2.

  Blood samples were collected at predetermined time points after the third oral dose and plasma levels of levodopa, carbidopa and 3-OMD were analyzed by HPLC-ECD.

  FIG. 5 shows Sinemet (oral 100/25 LD) with continuous SC administration of A) Entacapone (200 mg / 24 h) ± CD (40 mg / 24 h) or B) Levodopa (140 mg / 24 h) ± CD (40 mg / 24 h) in pigs. / CD) shows the average levodopa plasma concentration after oral administration (all subcutaneous formulations contained arginine as described above).

The results show that levodopa plasma PK (ng when continually administered subcutaneously compared to the calculated LD plasma PK obtained after adding the plasma concentration of LD after continuous SC administration of CD and entacapone respectively. / Ml), there is a synergistic effect between Entacapone (200 mg / 24 h) and CD (40 mg / 24 h) (FIG. 1A and Table 2, C vs B + D). The results also show that levodopa plasma PK when continuously administered subcutaneously compared to the calculated LD plasma PK obtained after adding plasma concentration of LD after continuous SC administration of CD and LD respectively. ng / ml), showing an additional effect between levodopa (140 mg / 24 h) and CD (40 mg / 24 h) (FIG. 1B and Table 2, E vs. D + F). Furthermore, the results suggest that continuous SC administration of LD and CD may be sufficient to maintain a constant continuous levodopa plasma concentration even in the absence of oral LD / CD administration. (Dotted line in FIG. 5B and “E minus A” in Table M). Table M shows the trough concentrations of plasma levodopa ⁶ _1/2 and 8h after oral LD / CD administration.

  FIG. 6 shows a tissue biopsy from the application site of the levodopa-carbidopa arginine combination formulation as well as the levodopa / arginine formulation. No visible tissue irritation or damage was seen in the levodopa-carbidopa arginine formulation. The site where the levodopa-arginine formulation was administered appears to have some degree of blackening of the tissue. Without being limited to any theory, combining carbidopa and arginine with a levodopa (arginine) formulation prevents local oxidation of levodopa from local damage to levodopa by preventing oxidation of levodopa to irritating byproducts. It is conceivable to protect, and carbidopa is an effective antioxidant.

[Equivalent]
While specific embodiments of the subject invention have been described, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined with reference to the claims, their full scope of equivalents, and the specification, along with such variations.

  Unless otherwise specified, all numbers expressing amounts of ingredients, reaction conditions, etc. used in the specification and claims are understood to be modified in all cases by the term “about”. I want to be. Thus, unless indicated differently, the numerical parameters set forth in this specification and the appended claims are approximate numbers that can vary depending on the desired properties sought to be obtained by the present invention. It is.

[Incorporation by reference]
The entire contents of all patents, patent application publications, websites and other references cited herein are expressly incorporated herein by reference in their entirety.

FIG. 5 shows the effect of carbidopa on levodopa stability in vitro and ex vivo. FIG. 5 shows the effect of carbidopa on levodopa stability in vitro and ex vivo. FIG. 7 shows that the presence of 1% carbidopa in levodopa solution reduces the severity and extent of local levodopa-dependent subcutaneous toxicity in pigs. It is a graph which shows the effect of carbidopa on the pharmacokinetics of levodopa in pigs. It is a graph which shows the effect of carbidopa on the pharmacokinetics of levodopa in pigs. It is a graph which shows the effect of carbidopa on the pharmacokinetics of levodopa in pigs. FIG. 3 shows the effect of various agents on ex vivo levodopa oxidation in the subcutaneous tissue of porcine skin samples after subcutaneous administration of a levodopa / carbidopa formulation. FIG. 3 shows the effect of various agents on ex vivo levodopa oxidation in the subcutaneous tissue of porcine skin samples after subcutaneous administration of a levodopa / carbidopa formulation. FIG. 3 shows the effect of various agents on ex vivo levodopa oxidation in the subcutaneous tissue of porcine skin samples after subcutaneous administration of a levodopa / carbidopa formulation. FIG. 3 shows the effect of various agents on ex vivo levodopa oxidation in the subcutaneous tissue of porcine skin samples after subcutaneous administration of a levodopa / carbidopa formulation. Continuous subcutaneous (SC) entacapone (200 mg / 24 hours) and / or carbidopa (CD) (40 mg / ml) for plasma concentrations of levodopa (ng / ml) after oral administration of Sinemet (100/25 levodopa / carbidopa) in pigs 24 is a graph showing the effect of 24 hours). FIG. 4 is a graph showing the effect of continuous SC CD (40 mg / 24 hours) and / or levodopa (LD) (140 mg / 24 hours) administration on plasma concentrations of levodopa after oral administration of Sinemet (100/25) in pigs. . FIG. 5 shows the effect of carbidopa on local subcutaneous toxicity of levodopa after 24 hours of continuous subcutaneous administration at 0.16 ml / hour in pigs.

Claims (10)

  2.5% to 7% by weight of levodopa; 0% to 2% by weight carbidopa; 5% to 18% by weight arginine; and 0.25% to 3% by weight ascorbic acid or pharmaceutically A pharmaceutically acceptable composition comprising an acceptable salt.   The pharmaceutically acceptable composition of claim 1 having a pH of 9.1 to 9.8 at 25 ° C.   The pharmaceutically acceptable composition of claim 1, wherein the molar ratio of levodopa and carbidopa (if present) to arginine is from about 1: 1.8 to about 1: 3.5.   The pharmaceutically acceptable composition according to claim 1, wherein the salt of ascorbic acid is selected from ascorbate, sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, or ascorbyl stearate. .   The pharmaceutically acceptable composition according to any one of claims 1 to 4, further comprising an agent that inhibits the formation of oxidation products. Said agent, L- cysteine, N- acetylcysteine (NAC), glutathione _{(GSH), Na 2 -EDTA,} Na 2 -EDTA-Ca, is selected from sodium hydrogen sulfite or combinations thereof, to claim 5 The pharmaceutically acceptable composition described.   7. A pharmaceutically acceptable composition according to any one of the preceding claims, wherein the composition is prepared for continuous subcutaneous, transdermal, duodenal or intravenous administration.   8. A pharmaceutically acceptable composition according to any one of claims 1 to 7 for the treatment of neurological or movement disorders.   9. A pharmaceutically acceptable composition according to claim 8, wherein the neurological or movement disorder is Parkinson's disease.   The transdermal patch suitable for administration of the pharmaceutically acceptable composition as described in any one of Claims 1-6.